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Identifying an immunologic marker as a correlate of protection (CoP) for RSV vaccination is important. In the pivotal phase 3 trial, the mRNA-1345 vaccine demonstrated efficacy against RSV in older adults (NCT05127434). Here, we evaluate neutralizing antibodies (nAb) against RSV-A and -B, and IgG binding antibodies (bAb) to RSV fusion antigens as correlates of risk (CoR) and CoP against the pivotal trial’s efficacy endpoints of RSV lower respiratory tract disease with ≥2 or ≥3 signs/symptoms (RSV-LRTD-2+ and −3 + ) and acute respiratory disease (RSV-ARD). Day 29 RSV nAb and prefusion (preF) IgG demonstrate consistent inverse correlates with RSV endpoint occurrence. Day 29 point estimates (95% CIs) of the hazard ratio of each endpoint (RSV-LRTD-2 + , RSV-LRTD-3 + , RSV-ARD) per 10-fold increase in RSV-A nAb are 0.44 (0.30-0.65), 0.41 (0.20-0.84), and 0.45 (0.28-0.71), respectively, similar to RSV-B nAb and preF IgG. These results demonstrate Day 29 RSV nAb and preF IgG are CoRs and support their role as CoPs against RSV endpoints. Identifying an immunologic marker as a correlate of protection (CoP) for RSV vaccination is important. Here, the authors demonstrate RSV neutralizing antibodies and RSV prefusion IgG binding antibodies as CoP for mRNA vaccination against RSV disease.

Introduction The randomized, placebo-controlled, double-blind MOVe-OUT trial demonstrated molnupiravir (800 mg every 12 h for 5 days) as safe and effective for outpatient treatment of mild-to-moderate COVID-19, significantly reducing the risk of hospitalization/death in high-risk adults. At the time of that report, virologic assessments from the trial were partially incomplete as a result of their time-intensive nature. Here we present final results from all prespecified virology endpoints in MOVe-OUT based on the full trial dataset. Methods Nasopharyngeal swabs were collected at baseline (day 1, prior to first dose) and days 3, 5 (end-of-treatment visit), 10, 15, and 29. From these samples, change from baseline in SARS-CoV-2 RNA titers (determined by quantitative PCR), detection of infectious SARS-CoV-2 (by plaque assay), and SARS-CoV-2 viral error induction (determined by whole genome next-generation sequencing) were assessed as exploratory endpoints. Results Molnupiravir was associated with greater mean reductions from baseline in SARS-CoV-2 RNA than placebo (including 50% relative reduction at end-of-treatment) through day 10. Among participants with infectious virus detected at baseline ( n  = 96 molnupiravir, n  = 97 placebo) and evaluable post-baseline samples, no molnupiravir-treated participant had infectious SARS-CoV-2 by day 3, whereas infectious virus was recovered from 21% of placebo-arm participants on day 3 and 2% at end-of-treatment. Consistent with molnupiravir’s mechanism of action, sequence analysis demonstrated that molnupiravir was associated with an increased number of low-frequency transition errors randomly distributed across the SARS-CoV-2 RNA genome compared with placebo (median 143.5 molnupiravir, 15 placebo), while transversion errors were infrequent overall (median 2 in both arms). Outcomes were consistent regardless of baseline SARS-CoV-2 clade, presence of SARS-CoV-2-specific immune response, or viral load. Conclusions A 5-day course of orally administered molnupiravir demonstrated a consistently greater virologic effect than placebo, including rapidly eliminating infectious SARS-CoV-2, in high-risk outpatients with mild-to-moderate COVID-19. Trial Registration ClinicalTrials.gov, NCT04575597.

Oral outpatient treatment for Covid-19 is needed. In this phase 3, double-blind, randomized, controlled trial, molnupiravir, a small-molecule antiviral, was studied in unvaccinated patients with less than 5 days of Covid-19 illness. By day 29, hospitalization for progression of Covid-19 was lower with molnupiravir (6.8%) than with placebo (9.7%).

In a placebo-controlled, phase 2–3 trial, one dose of mRNA-1345 led to a lower incidence of RSV disease among adults 60 years of age or older. Solicited local and systemic adverse reactions occurred more often with the vaccine.

Purpose Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. Methods In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. Results Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5:  – 0.31, 95% confidence interval [CI]  – 0.47 to  – 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI  – 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir’s mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. Conclusion Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. ClinicalTrials.gov Registration Number NCT04575597.

Coadministration of a respiratory syncytial virus (RSV) vaccine with seasonal influenza or SARS-CoV-2 vaccines could reduce health-care visits and increase vaccination uptake in older adults who are at high risk for severe respiratory disease. The RSV mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in the ConquerRSV trial in adults aged 60 years and older. We aimed to evaluate the safety and immunogenicity of mRNA-1345 coadministered with a seasonal influenza vaccine or SARS-CoV-2 mRNA vaccine. We conducted a two-part, phase 3, observer-blinded, placebo-controlled, randomised trial in medically stable adults aged 50 years or older in the USA. In part A, participants were randomly assigned in a 7:10:10 ratio to receive 50 μg mRNA-1345 plus placebo (0·9% sodium chloride) or coadministered with 60 μg of a standard-dose quadrivalent inactivated influenza vaccine (SIIV4), or SIIV4 plus placebo. In part B, participants were randomly assigned in a 1:1:1 ratio to receive 50 μg mRNA-1345 plus placebo or coadministered with 50 μg SARS-CoV-2 mRNA-1273.214 (bivalent [Wuhan-Hu-1 plus omicron BA.1]), or mRNA-1273.214 plus placebo. Random allocation in both parts was stratified by age group (50–59 years, 60–74 years, and ≥75 years) and used interactive response technology. The coprimary objectives in each part were safety in the safety set throughout the study and non-inferiority for six immunogenicity endpoints in the per-protocol set comparing coadministered versus individual vaccines on day 29. Immunogenicity endpoints were geometric mean titre (GMT) ratios (GMRs) of RSV-A neutralising antibodies (nAbs; in parts A and B), GMRs of haemagglutination inhibition (HAI) titres to each of the four influenza strains in SIIV4 (A/Victoria/2570/2019 [H1N1]pdm09-like virus [A/H1N1], A/Cambodia/e0826360/2020 [H3N2]-like virus [A/H3N2], B/Washington/02/2019-like virus [B/Victoria], and B/Phuket/3073/2013-like virus [B/Yamagata]; in part A), GMRs of nAbs against SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B), and differences in seroresponse rates for nAbs against RSV-A (parts A and B) and SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B). Non-inferiority was declared when the lower bound of the 95% CI for GMRs was greater than 0·667 and for seroresponse rate differences was greater than −10%. This trial is registered with ClinicalTrials.gov (NCT05330975) and is ongoing. Between April 1 and June 9, 2022, 1631 participants were randomly allocated in part A and 1623 received vaccinations on day 1 (685 [42%] received mRNA-1345 plus SIIV4, 249 [15%] mRNA-1345 plus placebo, and 689 [42%] SIIV4 plus placebo). Due to an interactive response technology error, the mRNA-1345 plus placebo group was smaller than planned (249 vs 420 participants). Of the 1623 participants in the safety set, 877 (54%) were female and 746 (46%) were male. Between July 27 and Sept 28, 2022, 1691 participants were randomly allocated in part B and 1681 received vaccinations on day 1 (564 [34%] received mRNA-1345 plus mRNA-1273.214, 558 [33%] mRNA-1345 plus placebo, and 559 [33%] mRNA-1273.214 plus placebo). Among the 1681 participants in the safety set, 924 (55%) were female and 757 (45%) were male. The reactogenicity profiles of the coadministered regimens were generally similar to the profiles when the vaccines were administered alone. As of the 6-month and 7-month follow-up times for parts A and B, respectively, no serious adverse events, adverse events of special interest, discontinuations due to adverse events, or fatal events considered related to study vaccination were reported. In part A, the GMR of nAbs against RSV-A in the mRNA-1345 plus SIIV4 group versus the mRNA-1345 alone group was 0·81 (95% CI 0·67 to 0·97), and the seroresponse rate difference in nAbs against RSV-A between the groups was −11·2% (95% CI −17·9 to −4·1). GMRs of anti-HAI titres in the mRNA-1345 plus SIIV4 versus SIIV4 alone groups were 0·89 (0·77 to 1·03) for A/H1N1, 0·97 (0·86 to 1·09) for A/H3N2, 0·93 (0·82 to 1·05) for B/Victoria, and 0·91 (0·81 to 1·02) for B/Yamagata. In part B, the GMR of nAbs against RSV-A in the mRNA-1345 plus mRNA-1273.214 versus the mRNA-1345 alone groups was 0·80 (95% CI 0·70 to 0·90), and the seroresponse rate difference was –4·4% (95% CI –9·9 to 1·0). Comparing the mRNA-1345 plus mRNA-1273.214 group with the mRNA-1273.214 alone group, the GMR of nAbs was 0·96 (0·87 to 1·06) for the ancestral (D614G) virus and 1·00 (0·89 to 1·14) for omicron BA.1; seroresponse rate differences were 0·2% (95% CI –6·0 to 6·3) for SARS-CoV-2 ancestral and –0·9% (–6·6 to 4·7) for omicron BA.1. Coadministered mRNA-1345 plus SIIV4 or mRNA-1273.214 vaccines had acceptable safety profiles and elicited mostly non-inferior immune responses compared to individual vaccines in adults aged 50 years or older; only the seroresponse rate difference in nAbs against RSV-A in part A did not meet the non-inferiority criterion. Overall, these data support coadministration of mRNA-1345 with these vaccines in this population; longer-term evaluation continues in this study. Moderna.

We consider the problem of comparing sizes and shapes of objects when landmark data are prone to measurement error. We show that naive implementation of ordinary Procrustes analysis that ignores measurement error can compromise inference. To account for measurement error, we propose the conditional score method for matching configurations, which guarantees consistent inference under mild model assumptions. The effects of measurement error on inference from naive Procrustes analysis and the performance of the proposed method are illustrated via simulation and application in three real data examples. Supplementary materials for this article are available online.